The present invention relates to the potentiation of glutamate receptor function using certain cyclopentyl sulfonamide derivatives. It also relates to cyclopentyl sulfonamide novel derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins and Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed xe2x80x9cionotropicxe2x80x9d. This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked xe2x80x9cmetabotropicxe2x80x9d excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
AMPA receptors are assembled from four protein sub-units known as GluR1 to GluR4, while kainic acid receptors are assembled from the sub-units GluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer, Molecular Pharmacology 44: 505-510, 1993. It is not yet known how these sub-units are combined in the natural state. However, the structures of certain human variants of each sub-unit have been elucidated, and cell lines expressing individual sub-unit variants have been cloned and incorporated into test systems designed to identify compounds which bind to or interact with them, and hence which may modulate their function. Thus, European patent application, publication number EP-A2-0574257 discloses the human sub-unit variants GluR1B, GluR2B, GluR3A and GluR3B. European patent application, publication number EP-A1-0583917 discloses the human sub-unit variant GluR4B.
One distinctive property of AMPA and kainic acid receptors is their rapid deactivation and desensitization to glutamate. Yamada and Tang, The Journal of Neuroscience, September 1993, 13(9): 3904-3915 and Kathryn M. Partin, J. Neuroscience, Nov. 1, 1996, 16(21): 6634-6647. The physiological implications of rapid desensitization, and deactivation if any, are not fully understood.
It is known that the rapid desensitization and deactivation of AMPA and/or kainic acid receptors to glutamate may be inhibited using certain compounds. This action of these compounds is often referred to in the alternative as xe2x80x9cpotentiationxe2x80x9d of the receptors. One such compound, which selectively potentiates AMPA receptor function, is cyclothiazide. Partin et al., Neuron. Vol. 11, 1069-1082, 1993. Compounds which potentiate AMPA receptors, like cyclothiazide, are often referred to as ampakines.
International Patent Application Publication Number WO 9625926 discloses a group of phenylthioalkylsulphonamides, S-oxides and homologs which are said to potentiate membrane currents induced by kainic acid and AMPA.
Ampakines have been shown to improve memory in a variety of animal tests. Staubli et al., Proc. Natl. Acad. Sci., Vol. 91, pp 777-781, 1994, Neurobiology, and Arai et al., The Journal of Pharmacology and Experimental Therapeutics, 278: 627-638, 1996.
In addition, certain sulfonamide derivatives which potentiate glutamate receptor function in a mammal have been disclosed in International Patent Application Publication WO 98/33496 published Aug. 6, 1998 and International Patent Application Publication WO 99/43285 published Sep. 2, 1999.
It has now been found that cyclopentyl derivatives of the present invention are surprisingly potent potentiators of glutamate receptor function.
The present invention provides compounds of formula I: 
wherein
R1, R2, and R3 each independently represent hydrogen, halogen, CF3, OCF3, CN, NO2, NH2, (1-6C)alkyl, (1-6C)alkoxy, xe2x80x94(CH2)nNHSO2R5, xe2x80x94(CH2)nNNHC(xe2x95x90O)R5, xe2x80x94SO2R5, xe2x80x94C(xe2x95x90O)R6, xe2x80x94CHxe2x95x90CHCO2R7, heterocycle, or phenyl which is unsubstituted or substituted by one, two, or three substituents selected from the group consisting of halogen, CF3, OCF3, CN, NO2, NH2, (1-6C)alkyl, (1-6C)alkoxy, xe2x80x94(CH2)nNHSO2R5, xe2x80x94(CH2)nNHC(xe2x95x90O)R5, xe2x80x94SO2R5, xe2x80x94C(xe2x95x90O)R6, xe2x80x94C(xe2x95x90O)NR10R11, xe2x80x94SO2NR10R11, or xe2x80x94CHxe2x95x90CHCO2R7;
R4 represents (1-6C)alkyl, (2-6C)alkenyl, or NR8R9;
R5 represents (1-6C)alkyl, CF3, or phenyl which is unsubstituted or substituted by one, two, or three substituents selected from the group consisting of halogen, CF3, CN, NO2, NH2, (1-6C)alkyl, or (1-6C)alkoxy;
R6 represents (1-4C)alkyl or phenyl;
R7 represents hydrogen or (1-4C)alkyl;
R8 and R9 each independently represent hydrogen or (1-4C)alkyl;
R10 and R11 each independently represent hydrogen or (1-4C)alkyl; and
n is 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of potentiating glutamate receptor function in a patient requiring such treatment, which comprises administering to said patient an effective amount of a compound of formula I.
In addition, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for potentiating glutamate receptor function.
The invention further provides pharmaceutical compositions comprising, a compound of formula I and a pharmaceutically acceptable diluent or carrier.
According to another aspect, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for potentiating glutamate receptor function.
The present invention provides a method of treating cognitive disorders in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
In addition, the present invention further provides a method of treating cognitive deficits associated with psychosis in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
This invention also encompasses novel intermediates, and processes for the synthesis of the compounds of formula I.
In this specification, the term xe2x80x9cpotentiating glutamate receptor functionxe2x80x9d refers to any increased responsiveness of glutamate receptors, for example AMPA receptors, to glutamate or an agonist, and includes but is not limited to inhibition of rapid desensitization or deactivation of AMPA receptors to glutamate.
A wide variety of conditions may be treated or prevented by compounds of formula I and their pharmaceutically acceptable salts through their action as potentiators of glutamate receptor function. Such conditions include those associated with glutamate hypofunction, such as psychiatric and neurological disorders, for example cognitive disorders and neuro-degenerative disorders such as Alzheimer""s disease; age-related dementias; age-induced memory impairment; cognitive deficits due to autism, Down""s syndrome and other central nervous system disorders with childhood onset, cognitive deficits post electroconvulsive therapy, movement disorders such as tardive dyskinesia, Huntington""s chorea, myoclonus, dystonia, spasticity, and Parkinson""s disease; reversal of drug-induced states (such as cocaine, amphetamines, alcohol-induced states); depression; attention deficit disorder; attention deficit hyperactivity disorder; psychosis; cognitive deficits associated with psychosis, drug-induced psychosis, stroke, and sexual dysfunction. Compounds of formula I may also be useful for improving memory (both short term and long term) and learning ability. The present invention provides the use of compounds of formula I for the treatment of each of these conditions.
It is understood that the trans and cis compounds of formulas Ixe2x80x2 and Ixe2x80x3 as represented below are included within the scope of the present invention, including the individual enantiomers thereof: 
As used herein the term xe2x80x9cheterocyclexe2x80x9d refers to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated or unsaturated, and consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized and including a bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which affords a stable structure.
Examples of such heterocycles include piperidinyl, piperazinyl, azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl-sulfone, oxadiazolyl, triazolyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.
As used herein, the terms xe2x80x9chalogenxe2x80x9d, xe2x80x9chaloxe2x80x9d, xe2x80x9chalidexe2x80x9d or xe2x80x9cHalxe2x80x9d refers to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified.
As used herein the term xe2x80x9c(1-6C)alkylxe2x80x9d refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term xe2x80x9c(1-6C)alkylxe2x80x9d includes within its definition the term xe2x80x9c(1-4C)alkylxe2x80x9d.
As used herein the term xe2x80x9c(2-6C)alkenylxe2x80x9d refers to a straight or branched, monovalent, unsaturated aliphatic chain having from two to six carbon atoms. Typical (2-6C)alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like. The term xe2x80x9c(2-6C)alkenylxe2x80x9d includes within its definition the term xe2x80x9c(2-4C)alkenylxe2x80x9d.
As used herein the term xe2x80x9c(1-6C)alkoxyxe2x80x9d refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical (1-6C)alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term xe2x80x9c(1-6C)alkoxyxe2x80x9d includes within its definition the term xe2x80x9c(1-4C)alkoxyxe2x80x9d.
As used herein, the term xe2x80x9cMexe2x80x9d refers to a methyl group, the term xe2x80x9cEtxe2x80x9d refers to an ethyl group, the term xe2x80x9cPrxe2x80x9d refers to a propyl group, the term xe2x80x9ciPrxe2x80x9d refers to an isopropyl group and the term xe2x80x9cPhxe2x80x9d refers to a phenyl group.
The present invention includes the pharmaceutically acceptable salts of the compounds defined by formula I. A compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein, refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts. Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19 (1977) which are known to the skilled artisan.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, propionate, phenylpropionate, salicylate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, mandelate, nicotinate, isonicotinate, cinnamate, hippurate, nitrate, phthalate, teraphthalate, butyne-1,4-dioate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, phthalate, p-toluenesulfonate, p-bromobenzenesulfonate, p-chlorobenzenesulfonate, xylenesulfonate, phenylacetate, trifluoroacetate, phenylpropionate, phenylbutyrate, citrate, lactate, a-hydroxybutyrate, glycolate, tartrate, benzenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate, tartarate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, oxalic acid and methanesulfonic acid.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that the above salts may form hydrates or exist in a substantially anhydrous form.
As used herein, the term xe2x80x9cstereoisomerxe2x80x9d refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term xe2x80x9cenantiomerxe2x80x9d refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term xe2x80x9cchiral centerxe2x80x9d refers to a carbon atom to which four different groups are attached. As used herein, the term xe2x80x9cdiastereomersxe2x80x9d refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as xe2x80x9cepimersxe2x80x9d. The terms xe2x80x9cracematexe2x80x9d, xe2x80x9cracemic mixturexe2x80x9d or xe2x80x9cracemic modificationxe2x80x9d refer to a mixture of equal parts of enantiomers.
The term xe2x80x9cenantiomeric enrichmentxe2x80x9d as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or xe2x80x9ceexe2x80x9d, which is found using the following equation:   ee  =                              E          1                -                  E          2                                      E          1                +                  E          2                      xc3x97    100  
wherein E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 70:30 is achieved, the ee with respect to the first enantiomer is 40%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred.
Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. In addition, separation and isolation of the compounds of the present invention into the individual enantiomers is similarly performed by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column, or other standard resolving techniques. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of the present invention can be resolved using standard techniques such as those described by J. Jacques, et al., xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc., 1981, and E. L. Eliel and S. H. Wilen,xe2x80x9d Stereochemistry of Organic Compoundsxe2x80x9d, (Wiley-Interscience 1994), and European Patent Application No. EP-A-838448, published Apr. 29, 1998.
Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
The terms xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term xe2x80x9cRxe2x80x9d (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term xe2x80x9cSxe2x80x9d (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in xe2x80x9cNomenclature of Organic Compounds: Principles and Practicexe2x80x9d, (J. H. Fletcher, et al., eds., 1974) at pages 103-120.
The designation xe2x80x9cxe2x80x9d refers to a bond that protrudes forward out of the plane of the page.
The designation xe2x80x9cxe2x80x9d refers to a bond that protrudes backward out of the plane of the page.
The designation xe2x80x9cxe2x80x9d refers to a bond wherein the stereochemistry is not defined.
The compounds of structures (4) and (6) can be prepared following the procedures set forth in Scheme I below. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.

In Scheme I, step A, the cyclopentene of structure (1) is converted to the borane of structure (2) under standard conditions. For example, cyclopentene (1) is dissolved in a suitable organic solvent, such as dry methylene chloride under an atmosphere of nitrogen and cooled to about 0xc2x0 C. The solution is treated with about 0.5 equivalents of monochloroborane-methyl sulfide. The reaction mixture is allowed to warm to room temperature and stirred for about 8 to 16 hours. The solvent is removed under vacuum under a nitrogen atmosphere to provide borane (2).
In Scheme I, step B, borane (2) is methylated to provide the methylborane of structure (3). For example borane (2) is dissolved in a suitable organic solvent, such as dry hexanes under an atmosphere of nitrogen. The solution is cooled to about 0xc2x0 C. and treated with about 0.3 equivalents of trimethylaluminum in hexanes. The reaction mixture is allowed to warm to room temperature and stirred for about 1.5 hours. A precipitate results and the supernatant is transferred via cannula to a nitrogen flushed separatory funnel containing saturated aqueous ammonium chloride. The organic phase is then transferred via cannula to a flask containing anhydrous sodium sulfate. The organic solution is then transferred via cannula to a dry, nitrogen flushed flask and the solvent is removed under vacuum in the presence of a nitrogen atmosphere to provide the methylated borane (3).
In Scheme I, step C, the methylated borane (3) is hydrolyzed to the trans-cyclopentylamine of structure (4). For example, methylated borane (3) is dissolved in a suitable organic solvent, such as dry tetrahydrofuran and cautiously treated in small portions with a slight excess of hydroxylamine-O-sulfonic acid (referred to herein as xe2x80x9cHASxe2x80x9d) dissolved in tetrahydrofuran. The reaction is exothermic. After addition is complete, the reaction mixture is stirred for about 24 hours and then filtered. The filtrate is concentrated under vacuum and the residue is treated with concentrated HCl:methanol:water:diethyl ether (30:15:20:60, by volume). The mixture is stirred at room temperature for about 30 minutes. The layers are separated, the organic phase is washed with water and the water wash is combined with the aqueous phase. The aqueous phase is cooled to about 0xc2x0 C., diethyl ether is added and the aqueous is made basic with sodium hydroxide. The organic phase is separated and the aqueous phase is extracted with diethyl ether and ethyl acetate. The organic phase and organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the cyclopentylamine (4).
In Scheme I, step D, the cyclopentene of structure (1) is nitrated under standard conditions to provide the compound of structure (5). For example, see the procedure disclosed by F. G. Bordwell, et al., J. Org. Chem., 1765.
In Scheme I, step E, the nitrated compound of structure (5) is reduced under standard conditions to provide the amine of structure (6). For example, compound (5) is dissolved in a suitable organic solvent, such as ethanol, treated with a suitable hydrogenation catalyst, such as palladium on carbon, the solution is placed under hydrogen at about 413.69 kPa (60 psi). After about 8 to 16 hours, the reaction mixture is filtered and the filtrate is concentrated under vacuum to provide the compound (6).
The compound of structure (6) can be prepared by the alternative procedures set forth in Schemes IA and IB below. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined. 
In Scheme IA, step A, the cyclopentanone of structure (7) is converted to the corresponding oxime of structure (8) under conditions well known in the art. For example, cyclopentanone (7) is dissolved in a suitable organic solvent, such as ethanol, treated with about 2 equivalents of aqueous sodium hydroxide and about 1.5 equivalents of hydroxylamine hydrochloride. The reaction mixture is stirred for about 8 to 16 hours at room temperature. It is then diluted with water and the precipitated oxime (8) is collected by filtration and dried under vacuum at about 35xc2x0 C.
In Scheme IA, step B, oxime (8) is hydrogenated under standard conditions to provide the amine of structure (6). For example, oxime (8) is dissolved in a suitable organic solvent, such as ethanol, treated with a suitable catalyst, such as palladium on carbon, and placed under hydrogen at about 413.69 kPa (60 psi). The hydrogenation is carried out at about 40xc2x0 C. for about 8 to 16 hours. The reaction mixture is then filtered and the filtrate concentrated under vacuum to provide the amine (8). 
In Scheme IB, step A, the epoxide (9) is coupled with the Grignard reagent to provide the alcohol (11). For example, Grignard (10) is dissolved in a suitable organic solvent, such as tetrahydrofuran and treated with a catalytic amount of copper iodide. To this solution is slowly added the epoxide (9) dissolved in tetrahydrofuran. The reaction is exothermic. The reaction is stirred until the temperature reaches room temperature and it is quenched with aqueous ammonium chloride. The quenched reaction is extracted with a suitable organic solvent, such as diethyl ether. The organic extracts are combined, washed with aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide alcohol (11).
In Scheme IB, step B, alcohol (11) is converted to the compound of structure (12) under standard conditions well known in the art. For example, about one equivalent of triphenylphosphine is dissolved in a suitable organic solvent, such as tetrahydrofuran. The solution is cooled to about 0xc2x0 C. and a solution of about one equivalent of diisopropyl azodicarboxylate in tetrahydrofuran is added dropwise to the solution with stirring. To this reaction mixture is added about one equivalent of phthalimide followed by addition of about one equivalent of alcohol (11) dissolved in tetrahydrofuran maintaining the temperature between about 5xc2x0 C. and 0xc2x0 C. The reaction is then stirred at about 0xc2x0 C. for about 4 hours, warmed to room temperature, and stirred for 4 to 12 hours. The reaction is then quenched with water and extracted with a suitable organic solvent, such as chloroform. The organic extracts are combined, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide compound (12).
In Scheme IB, step C, compound (12) is converted to compound (6) in an exchange reaction well known in the art. For example, compound (12) is dissolved in a suitable organic solvent, such as toluene, and an excess of anhydrous hydrazine is added dropwise over about 15 minutes with stirring. The reaction mixture is stirred for about one hour at room temperature and then heated at about 90-95xc2x0 C. for about 6 hours. The reaction mixture is then cooled to room temperature, filtered, the precipitate rinsed with toluene, the filtrates combined, concentrated under vacuum to provide compound (6).
Alternatively, compound (12) is dissolved in 2-aminoethanol and heated at about 80-90xc2x0 C. for about 1 to 2 hours. The reaction is then diluted with diethyl ether, washed with dilute sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to provide compound (6).
In Scheme IB, step D, compound (11) oxidized to the ketone of structure (7) under standard conditions well known in the art. For example, compound (11) is added dropwise to a suspension of an excess of pyridinium chlorochromate in a suitable organic solvent, such as methylene chloride. The reaction is stirred for about 8 to 48 hours at room temperature. It is then diluted with a diethyl ether, filtered through a pad of silica gel and the filtrate concentrated under vacuum to provide crude compound (7). This material can be purified by standard techniques, such as flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane.
In Scheme IB, steps E through H, compound (11) is converted to the amine (4) using standard techniques and reactions well known in the art. For example, in step E, compound (11) is subjected to Mitsunobu conditions to provide the cis-benzoate derivative. More specifically, compound (11) is dissolved in a suitable organic solvent, such as THF and combined with about 1.05 equivalents of diethyl azodicarboxylate (referred to herein as xe2x80x9cDEADxe2x80x9d), about 1.2 equivalents of benzoic acid and about 1.2 equivalents of triphenylphosphine at about 0xc2x0 C. The reaction is stirred for about 2 hours, allowed to warm to room temperature and then concentrated under vacuum. The crude residue can be purified by chromatography on silica gel with a suitable eluent, such as hexanes/methylene chloride to provide the cis-benzoate derivative.
In Scheme IB, step F, the cis-benzoate is hydrolyzed under standard conditions to provide the cis-alcohol. For example, the cis-benzoate is combined with 5% NaOH/methanol and stirred at room temperature for about 3 hours. The reaction mixture is then concentrated under vacuum, the residue dissolved in a suitable organic solvent, such as diethyl ether, which is washed with water. The organic phase is then dried over potassium carbonate, filtered, and concentrated under vacuum. The residue can be purified by chromatography on silica gel with a suitable eluent, such as hexanes/methylene chloride to provide the cis-alcohol.
In Scheme IB, step G, the cis-alcohol is converted to the phthalimide derivative in a manner analogous to the procedure described above in Scheme IB, step B.
In Scheme IB, step H, the phthalimide derivative is converted to the trans-amine (4) in a manner analogous to the procedure described above in Scheme IB, step C. 
In Scheme IC, the compound (11) is subjected to an enzymatic resolution to provide the unreacted optically active alcohol (11a) and the optically active acetate (11b). For example, see the procedure described by Seemayer and Schneider, Recl. Trav. Chim. Pays-Bas, 110, 171-174 (1991), xe2x80x9cEnzymatic Hydrolysis and Esterification. Routes to Optically Pure Cyclopentanolsxe2x80x9d. More specifically, the alcohol (11) is dissolved in a suitable organic solvent, such as tert-butyl methyl ether and combined with a suitable enzyme, such as Candida antartctica B lipase. With stirring, about 0.5 to about 0.6 equivalents of vinyl acetate is added and the reaction is stirred at room temperature for about 2 to 4 hours. The reaction mixture is then filtered and the filtrated is concentrated under vacuum to provide a mixture of the optically active alcohol (11a) and optically active acetate (11b). These compounds are then readily separated from each other using standard techniques well known in the art, such as flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane.
The compounds of formulas I, Ia, Iaxe2x80x2, Iaxe2x80x3, and Ib can be prepared following the procedures set forth in Schemes II and IIA below. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined. 
In Scheme II, step A, compound (4) or (6) is sulfonylated with sulfonyl chloride (13) under conditions well known in the art to provide the sulfonamide of formula (Ia). For example, compound (4) or (6) is dissolved in a suitable organic solvent, such as methylene chloride and cooled to about 0xc2x0 C. under an atmosphere of nitrogen. About 1.1 equivalents of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added followed by dropwise addition of about 1.1 equivalents of a sulfonyl chloride (13). The reaction mixture is then allowed to warm to room temperature and stirred for about 8 to 24 hours. Additional small amounts of DBU and sulfonyl chloride (9) may optionally be added in equivalent amounts as necessary in order to drive the reaction to completion. The reaction may be stirred for an additional 8 to 48 hours after additional amounts of DBU and sulfonyl chloride (13) are added. The reaction mixture is then diluted with a suitable organic solvent, such as methylene chloride and washed with 1N HCl. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude compound of formula I. This crude material can be purified by standard techniques, such as flash chromatography or radial chromatography on silica gel with a suitable eluent, such as methylene chloride/ethyl acetate.
In Scheme II, step B, the compound of formula I wherein R1, R2 and R3 represent hydrogen, can be converted to the compound of formula Ia wherein Y represents iodine. For example, compound of formula I is dissolved in a suitable solvent, such as glacial acetic acid. To this solution is added concentrated sulfuric acid followed by about 0.5 equivalents of iodine and about 0.4 equivalents of diiodine pentoxide. The reaction mixture is protected from light and heated at about 90xc2x0 C. for about 22 hours. The reaction mixture is then treated slowly with 10% aqueous sodium bisulfite, cooled to 0xc2x0 C. for about one hour and the precipitate collected by filtration. The precipitate is dissolved in a suitable organic solvent, such as warm diethyl ether and then washed with water, saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the iodo compound of formula Ia. Alternatively, one of R1, R2 or R3 may represent Br in Scheme II, step A. In Scheme II, step C, the compounds of formula Ia, wherein Y represents Br or I, may be converted into compounds of formula Ib under conditions well known in the art, such as by reaction with an appropriate boronic acid (14) or boronic ester (14a) wherein R10, R11 and R12 each individually represent hydrogen, halogen, CF3, CN, NO2, NH2, (1-6C)alkyl, (1-6C)alkoxy, xe2x80x94(CH2)nNHSO2R5, xe2x80x94(CH2)nNHC(xe2x95x90O)R5, or xe2x80x94SO2R5. See for example, International Publication Number WO 98/33496, published Aug. 6, 1998, the disclosure of which is hereby incorporated by reference. In addition, see Suzuki, A., Journal of Organometallic Chemistry, 576, 147-168 (1999), and Miyaura and Suzuki, Chemical Reviews, 95, 2457-2483 (1995) for examples of Suzuki-type coupling reactions and conditions. More specifically, the reaction is conveniently performed in the presence of a tetrakis (triarylphosphine)palladium(0) catalyst, such as tetrakis (triphenylphosphine)palladium(0) and a base such as potassium carbonate. Suitable solvents for the reaction include aromatic hydrocarbons, such as toluene. The temperature at which the reaction is conducted is conveniently in the range of from 0 to 150xc2x0 C., preferably 75 to 120xc2x0 C. Alternatively, the coupling reaction may be carried out using palladium diacetate with a suitable organic solvent, such as n-propanol or acetone. See for example, Organic Synthesis 1998, 75, 61; Goodson, F. E.; Wallow, T. I.; Novak, B. M. and Organic Synthesis 1998, 75, 53; Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, M. A. wherein analogous coupling conditions are employed.
More specifically, for example, a compound of formula Ia and about 1.2 equivalents of boronic acid (14) or boronic ester (14a) are dissolved in a suitable organic solvent, such as n-propanol. About 1.2 equivalents of potassium carbonate in water is added, followed by a catalytic amount of palladium acetate. The reaction mixture is heated at reflux for about 4 hours, filtered and the solid rinsed with ethyl acetate. The filtrates are combined, diluted with additional ethyl acetate, and washed with saturated sodium bicarbonate and brine. The organic phase is then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude compound of formula Ib. This crude material can then be purified by techniques well known in the art, such as flash chromatography or radial chromatography on silica gel with a suitable eluent, such as methylene chloride/ethyl acetate or reverse phase chromatography on a C18 column with a suitable eluent, such as aqueous acetonitrile.
Alternatively, compounds of formula Iaxe2x80x2
wherein Q represents a bromo or triflate group may be coupled to boronic acid (14) in a manner analogous to the procedures set forth above in Scheme II, step C.
The boronic acid (14) used as a starting material may be prepared by reacting a trialkyl borate, such as triisopropyl borate with an appropriate organolithium compound at reduced temperature. For example, 2-fluoro-benzeneboronic acid may be prepared by reacting 2-fluorobromobenzene with butyllithium in tetrahydrofuran at about xe2x88x9278xc2x0 C. to afford 2-fluorophenyl lithium, and then reacting this organolithium compound with triisopropyl borate. This is followed by hydrolysis with aqueous HCl. 
Alternatively, compounds of formula Ib can be prepared under Suzuki-type reaction conditions as appreciated by one of ordinary skill in the art, from a compound of formula Iaxe2x80x3 and a compound of structure (14b). For example, the compound of formula Iaxe2x80x3 is dissolved in a suitable organic solvent, such as DMSO and treated with about 3 equivalents of potassium acetate. The reaction mixture is degassed and treated with about 1.1 equivalents of bis(pinacolato)diboron followed by addition of a catalytic amount of a suitable palladium catalyst, such as [1,1xe2x80x2-bis(diphenylphosphino)-ferrocene] dichloropalladium (II), complex with dichloromethane 1:1. The reaction mixture is then heated at about 80xc2x0 C. under nitrogen with stirring for about 1 to about 4 hours. The reaction mixture is then cooled to room temperature and about one equivalent of the compound (14b) is added followed by addition of about 3 equivalents of sodium carbonate, water, and a catalytic amount of a suitable palladium catalyst, such as [1,1xe2x80x2-bis(diphenylphosphino)-ferrocene] dichloropalladium (II), complex with dichloromethane 1:1. The reaction mixture is then heat at about 105xc2x0 C. for about 10 to about 20 hours. It is then allowed to cool and is diluted with a suitable organic solvent, such as methylene chloride. The mixture is washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the crude compound formula Ib. This crude material can then be purified by techniques well known in the art, such as chromatography on silica gel with a suitable eluent, such as 1% methanol/methylene chloride to provide the purified compound of formula Ib.
The compounds of formulas Ic and Id can be prepared following the procedures set forth in Scheme III below. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined. 
In Scheme III, step A compound of formula Ibxe2x80x2 wherein R10xe2x80x2 and R12xe2x80x2 each independently represent hydrogen, halogen, CF3, (1-6C)alkyl, or (1-6C)alkoxy and m is 0, 1, 2, or 3, is reduced under conditions well known in the art to provide the amine of formula Ic. For example, compound of formula Ibxe2x80x2 is dissolved in a suitable organic solvent, such as dry tetrahydrofuran and treated with a suitable reducing agent, such as borane dimethyl sulfide. The reaction is heated at reflux for about 4 hours and then concentrated under vacuum. The residue is treated with diethyl ether:concentrated HCl:water:methanol (6:3:2:1)and stirred for about 30 minutes. The aqueous layer is then separated and the organic layer washed with water. The aqueous phases are combined, cooled to about 0xc2x0 C., made basic with a suitable base, such as sodium hydroxide, and extracted with a suitable organic solvent, such as diethyl ether or ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the amine of formula Ic.
In Scheme III, step B, the amine of formula Ic is converted to the amide of formula Id under standard coupling conditions as is well known in the art of peptide chemistry. For example, the amine of formula Ic is dissolved in a suitable organic solvent, such as dry methylene chloride. A slight excess of a suitable organic base, such as triethylamine is added followed by addition of about one equivalent of acetyl chloride. The reaction is stirred at room temperature for about 8 to 72 hours and then concentrated under vacuum to provide the crude amide of formula Id. This crude material is then purified by standard techniques, such as flash chromatography or radial chromatography on silica gel with a suitable eluent, such as methylene chloride:methanol.
In Scheme III, step C, the amine of formula Ic is readily converted to the sulfonamide of formula Ie under standard conditions well known in the art, for example in a manner analogous to the procedure previously described in Scheme II, step A.
The compounds of formulas Ig, Ih, Ij and Ik can be prepared following the procedures set forth in Scheme IV below. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined. 
In Scheme IV, step A, the compound of formula If, wherein R1xe2x80x2 and R3xe2x80x2 each independently represent hydogen, halogen, CF3, (1-6C)alkyl, or (1-6C)alkoxy, is nitrated under standard conditions to provide the nitro compound of formula Ig. For example, compound of formula If is dissolved in a suitable acid, such as trifluoroacetic acid and an excess of sodium nitrate is added. The reaction mixture is stirred for about 5 hours at room temperature. It is then diluted with a suitable organic solvent, such as methylene chloride, washed with water, dilute sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude nitro compound of formula Ig. The crude material can then be purified using standard techniques such as flash chromatography or radial chromatography on silica gel with a suitable eluent, such as methylene chloride:ethyl acetate.
In Scheme IV, step B, the compound of formula Ig is reduced to the amine of formula Ih under conditions well known in the art. For example, the compound of formula Ig is dissolved in a suitable organic solvent, such as ethanol, treated with a suitable hydrogenation catalyst, such as palladium on carbon and placed under hydrogen at about 413.69 kPa (60 psi). The reaction mixture is hydrogenated at room temperature for about 4 to 12 hours, filtered, and concentrated under vacuum to provide the amine of formula Ih.
In Scheme IV, step C the amine of formula Ih is converted to the amide of formula Ij under standard coupling conditions as is well known in the art of peptide chemistry in a manner analogous to the procedure previously described in Scheme III, step B.
In Scheme IV, step D the amine of formula Ih is converted to the sulfonamide of formula Ik under standard conditions well known in the art, for example in a manner analogous to the procedure previously described in Scheme II, step A.
The compounds of formulas Im, In, Ip and Iq can be prepared following the procedures set forth in Scheme V below. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined. 
In Scheme V, step A, the compound of formula Iaxe2x80x2 is converted to the compound of formula Im under standard conditions. For example, compound of formula Iaxe2x80x2 is dissolved in a suitable organic solvent, such as DMF. It is then treated with an excess of ethyl acrylate and an excess of a suitable organic base, such as triethylamine followed by a catalytic amount of palladium acetate and triphenylphosphine. The reaction is then heated at about 80xc2x0 C. under nitrogen for about 8 to 16 hours. The reaction is then allowed to cool and diluted with 75 mL of 10% aqueous sodium bisulfate. The quenched reaction mixture is then extracted with a suitable organic solvent, such as methylene chloride, the organic extracts dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the compound of formula Im. The crude product can be purified by radial chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride.
In Scheme V, step B, the compound of formula Im is reduced under conditions well known in the art to provide the compound of formula In. For example, the compound of formula Im is placed in a Parr bottle and dissolved in a suitable organic solvent, such as ethyl acetate. It is treated with a catalytic amount of 10% palladium on carbon and the mixture is placed under hydrogen at about 275.80 kPa (40 psi) to about 413.69 kPa (60 psi) for about 4 to 16 hours at room temperature. The reaction is then filtered through diatomaceous earth and the filtrate is concentrated under vacuum to provide the compound of formula In. This material can be further purified, if necessary, for example by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexanes.
In Scheme V, step C, the compound of formula In is hydrolyzed to the acid of formula Ip under standard conditions. For example, the compound of formula In is dissolved in a suitable organic solvent, such as methanol with water added. The solution is treated with a suitable base, such as sodium hydroxide and the reaction is allowed to stir for about one to two days. The reaction mixture is then washed with a suitable organic solvent, such as ethyl acetate. The aqueous is cooled with an ice-water bath and made acidic with concentrated HCl. The acidified aqueous is then extracted with ethyl acetate, the organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the acid of formula Ip.
In Scheme V, step D, the acid of formula Ip is converted to the carbamate of formula Iq under standard conditions. For example, the acid of formula Ip is dissolved in a suitable organic solvent, such as benzene and is treated with one equivalent of diphenylphosphoryl azide and one equivalent of triethylamine under nitrogen. The reaction is heated at reflux for about 4 hours, cooled to room temperature and stirred for about 8 to 16 hours. An equivalent of a suitable alcohol, such as methanol or benzyl alcohol is then added to the reaction, and the reaction is heated at reflux for about 8 hours. The reaction is then cooled to room temperature and stirred for about 8 to 16 hours. The reaction is then concentrated under vacuum and the residue purified by flash or radial chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexanes.
In Scheme V, step E, the carbamate of formula Iq is deprotected under conditions well known in the art such as those conditions described by T. W. Green xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d John Wiley and Sons, 1981, pages 239-241, to provide the amine of formula Ir. For example, the carbamate of formula Iq is dissolved in a suitable organic solvent, such as methylene chloride and treated with trifluoroacetic acid. The reaction mixture is allowed to stir at room temperature for about 4 to 16 hours and then the solution is made basic with 2N sodium hydroxide. The reaction mixture is then extracted with a suitable organic solvent, such as ethyl acetate, the organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the amine of formula Ir. This material may be further purified by radial chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride. Alternatively, the carbamate of formula Iq may be deprotected using hydrogenation conditions well known in the art to provide the amine of formula Ir.
In Scheme V, step F, the amine of formula Ir is converted to the sulfonamide of formula It under standard conditions well known in the art, for example, in a manner analogous to the procedure described in Scheme II, step A above.
The following preparations and examples further illustrate the invention and represent typical syntheses of the compounds of formula I as described generally above. The reagents and starting materials are readily available to one of ordinary skill in the art. As used herein the term xe2x80x9cChromatotron(copyright)xe2x80x9d (Harrison Research Inc., 840 Moana Court, Palo Alto Calif. 94306) is recognized by one of ordinary skill in the art as an instrument which is used to perform centrifugal thin-layer chromatography. As used herein, the following terms have the meanings indicated: xe2x80x9ceqxe2x80x9d refers to equivalents; xe2x80x9cgxe2x80x9d refers to grams; xe2x80x9cmgxe2x80x9d refers to milligrams; xe2x80x9cLxe2x80x9d refers to liters; xe2x80x9cmLxe2x80x9d refers to milliliters; xe2x80x9cxcexcLxe2x80x9d refers to microliters; xe2x80x9cmolxe2x80x9d refers to moles; xe2x80x9cmmolxe2x80x9d refers to millimoles; xe2x80x9ckPaxe2x80x9d refers to kilopascals; xe2x80x9cpsixe2x80x9d refers to pounds per square inch; xe2x80x9cminxe2x80x9d refers to minutes; xe2x80x9chxe2x80x9d or xe2x80x9chrxe2x80x9d refers to hours; xe2x80x9cxc2x0 C.xe2x80x9d refers to degrees Celsius; xe2x80x9cTLCxe2x80x9d refers to thin layer chromatography; xe2x80x9cHPLCxe2x80x9d refers to high performance liquid chromatography; xe2x80x9cRfxe2x80x9d refers to retention factor; xe2x80x9cRtxe2x80x9d refers to retention time; xe2x80x9cxcex4xe2x80x9d refers to parts per million down-field from tetramethylsilane; xe2x80x9cTHFxe2x80x9d refers to tetrahydrofuran; xe2x80x9cPdCl2(dppf)xe2x80x9d refers to [1,1xe2x80x2 bis(diphenylphosphino)-ferrocene] dichloropalladium (II); xe2x80x9cMTBExe2x80x9d refers to tert-butyl methyl ether; xe2x80x9cDMFxe2x80x9d refers to N,N-dimethylformamide; xe2x80x9cDMSOxe2x80x9d refers to methyl sulfoxide; xe2x80x9cLDAxe2x80x9d refers to lithium diisopropylamide; xe2x80x9cEtOAcxe2x80x9d refers to ethyl acetate; xe2x80x9caqxe2x80x9d refers to aqueous; xe2x80x9ciPrOAcxe2x80x9d refers to isopropyl acetate; xe2x80x9cDBUxe2x80x9d refers to 1,8-diazabicyclo[5.4.0]undec-7-ene; xe2x80x9cDEADxe2x80x9d refers to diethyl azodicarboxylate; and xe2x80x9cRTxe2x80x9d refers to room temperature.

Scheme I, step A: Modification of H. C. Brown et. al., Tetrahedron Asymmetry, 7, 3527-3534 (1996). 1-Phenylcyclopentene (commercial 96%)(10.0 g, 69.4 mmol) was placed in an oven-dried flask under nitrogen and diluted with 60 mL of dry methylene chloride. The solution was cooled to 0xc2x0 C. and monochloroborane-methyl sulfide complex (3.6 mL, 34.7 mmoL) was added dropwise via syringe. The solution was allowed to warm to room temperature and stirred overnight. The solvent is removed by aspirator vacuum under a nitrogen atmosphere to provide a crude colorless oil. This oil is used directly in the next step without further characterization.

Scheme I, step B: Chloro-bis-(2-phenyl-cyclopentyl)-borane from preparation 1 was diluted with 60 mL of dry hexanes under nitrogen. The solution was cooled to 0xc2x0 C. and a 2M solution of trimethylaluminum in hexanes (5.8 mL) was added dropwise causing the reaction to turn orange. The reaction was allowed to warm to room temperature and stirred for 1.5 hours. During this time a red-brown mass precipitated out of solution, leaving a yellow supernatant. The hexane supernatant was transferred via cannula to a nitrogen flushed separatory funnel containing 50 mL of saturated aqueous ammonium chloride. The organic phase becomes colorless and was transferred via cannula to a dry flask containing sodium sulfate for drying. The solution was then transferred via cannula to a dry, nitrogen-flushed flask and the solvent removed under aspirator vacuum and nitrogen. The clear oil was used directly without further characterization.

Scheme I, step C: Methyl-bis-(2-phenyl-cyclopentyl)-borane (theoretical 34.7 mmoL) from preparation 2 was diluted with 40 mL of dry tetrahydrofuran. 8.3 g (72.9 mmol) of hydroxylamine-O-sulphonic acid (HSA) was slurried in a separate dry flask in 60 mL of THF and small portions are transferred via cannula to control the exothermic reaction. The cloudy white solution was stirred at room temperature for 24 hours. The reaction mixture was filtered and the THF removed in vacuo. The residue was treated with 30 mL of concentrated HCl, 15 mL of methanol, 20 mL of water and 60 mL of diethyl ether and stirred at room temperature for 30 minutes. The aqueous phase was collected and the organic phase washed with water and combined with the aqueous phase. The aqueous phase was cooled to 0xc2x0 C., layered with diethyl ether, and made strongly basic with sodium hydroxide pellets. The organic phase was separated and the aqueous phase extracted with diethyl ether (2xc3x97) and ethyl acetate (1xc3x97). The organic phases were combined and dried over sodium sulfate. The filtrate was concentrated to 5.96 (53%) of the title compound as a yellow oil.
Mass Spectrum (ES MS): M+1=162.

Scheme I, step D: (5-Nitro-cyclopent-1-enyl)-benzene was prepared according to the procedure of F. G. Bordwell et. al., J. Org. Chem., 1765-1769, 1963. The title compound was prepared by nitration of 1-phenylcyclopentene (3.0 g, 20.8 mmol) and purified by radial chromatography eluting with 85:15 hexanes:ethyl acetate to yield 0.63 g (12%) as a yellow oil. The NMR was consistent with the assigned structure.

Scheme I, step E: (5-Nitro-cyclopent-1-enyl)-benzene (0.63 g, 3.3 mmol) from preparation 4 above, was hydrogenated in 25 mL of ethanol using 0.16 g of 5% Pd/C at room temperature overnight at 413.69 kPa (60 psi). The solution was filtered over celite and concentrated in vacuo to 230 mg (43%) of the title compound as a colorless oil. The NMR was consistent with the assigned structure. Mass Spectrum (ES MS): M+1=162.

Scheme IA, step A: 2-Phenyl-cyclopentanone (prepared according to R. Sudha et. al. J. Org. Chem., 61, 1877-1879, 1996) (1.0 g, 6.2 mmol) was dissolved in 20 mL of absolute ethanol. To this solution was added sodium hydroxide (0.5 g, 12.5 mmol) dissolved in 10 mL water followed by hydroxylamine hydrochloride (0.65 g, 9.36 mmol) and stirred overnight at room temperature. The reaction was diluted with water and the precipitate collected by filtration. The white solid was vacuum oven-dried at 35xc2x0 C. for 30 minutes to give 0.75 g (69%) of the title compound. The NMR was consistent with the assigned structure.
Analysis calculated for C11H13NO: % C, 75.40; % H, 7.48; % N, 7.99. Found: % C, 75.32; % H, 7.22; % N, 7.92. Mass Spectrum (ES MS): M+1=176.

Scheme IA, step B: (+,xe2x88x92) 2-Phenyl-cyclopentanone oxime from preparation 6 above was dissolved in 35 mL of ethanol and hydrogenated using 90 mg of 5% Pd/C at 40xc2x0 C. overnight at 413.69 kPa (60 psi). The solution was filtered and concentrated in vacuo to give 0.43 g (62%) of a colorless oil. Some dimeric material resulted by this procedure according to the mass spec. The cis:trans ratio was estimated to be 4:1. The amine was used directly without further purification. The NMR was consistent with the assigned structure.
Mass Spectrum (ES MS): M+1=306, 162.

Scheme IB, step A: A one liter three necked round bottom flask equipped with a mechanical stirrer, addition funnel, thermometer is charged with 1M THF solution of phenylmagnesium bromide (300 mL, 300.0 mmol) and copper iodide (3.8 g, 20.0 mmol). To this reaction mixture was then added cyclopentene oxide (25.23 g, 300.0 mmol) dissolved in THF (50.0 mL) dropwise over a period of 60 minutes (reaction was quite exothermic, reaching THF reflux by the end of addition). The reaction mixture was then stirred to room temperature and quenched with 25% solution of ammonium chloride (200.0 mL). Added ether (80.0 mL) and separated upper organic layer. Washed organic layer with 25% ammonium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated filtrate to provide (+,xe2x88x92) trans-2-phenyl-cyclopentanol as a brown oil (mass =47.7 g);
1H nmr (CDCl3) xcex4 1.6-1.8 (m, 4H), 2.0-2.2 (m, 2H), 2.8-2.88 (m, 1H), 4.13-4.16 (m, 1H), 7.2-7.4 (aromatic, 5H); 13C (CDCl3) xcex4 22.46, 32.57, 34.64, 55.13, 81.11, 127.10, 128.11, 129.25, 144.05).
Scheme IB, step B: A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser, addition funnel and a nitrogen blanket is charged with triphenylphosphine (16.19 g, 61.73 mmol) and THF (200 mL). To the solution at 0xc2x0 C. was added dropwise, a solution of diisopropyl azodicarboxylate (12.15 mL, 61.73 mmol) dissolved in THF (30 mL) over a period of 10 minutes. A massive precipitate formed immediately after addition. To the slurry was then added solid phthalimide (9.08 g, 61.73 mmol), followed by a solution of 5-phenylcyclopentane-1-ol (10.0 g, 61.73 mmol) dissolved in THF (30 mL) over a period of 20 minutes maintaining temperature at 0xc2x0 C. to 5xc2x0 C. (reaction mixture went into solution by the end of alcoholic substrate addition). Reaction was then stirred at 0xc2x0 C. for 4.0 hours and brought to room temperature overnight for convenience. Quenched reaction with water (200 mL) and extracted organics with chloroform (200 mL). Washed the organic with water (100 mL) and dried with anhydrous magnesium sulfate. Subsequent filtration and concentration under reduced pressure afforded an oil which solidified on equilibrating to room temperature. To the precipitate was then added hexane (250.0 mL) with vigorous stirring. Filtered off triphenylphosphine oxide precipitate and concentrated filtrate to an oil. Silica gel plug filtration of the oil with 1:1 ethyl acetate:hexanes and subsequent concentration of product fractions afforded an off white precipitate of (+,xe2x88x92) Cis-2-(2-phenyl-cyclopentyl)-isoindole-1,3-dione (mass=12.5 g, 69.6%); 1H nmr (CDCl3) 6 1.6-1.8 (m, 1H), 2.0-2.1 (m, 1H), 2.2-2.35 (m, 2H), 2.4-2.68 (m, 2H), 3.39-3.5 (m, 1H), 5.0-5.1 (m, 1H), 6.9-7.15 (aromatic, 5H), 7.52-7.64 (aromatic, 4H); 13C (CDCl3) 6 25.4, 28.89, 30.56, 50.34, 54.60, 122.89, 126.44, 128.01, 128.41, 131.67, 139.68, 168.86).
Scheme IB, step C: A 1000 mL three necked flask equipped with a mechanical stirrer, thermometer, addition funnel and a reflux condenser is charged with (+,xe2x88x92) cis-2-(2-phenyl-cyclopentyl)-isoindole-1,3-dione (27.34 g, 93.91 mmol) and toluene (400.0 mL). To this solution was added anhydrous hydrazine (29.48 mL, 939.09 mmol) dropwise over a period of 15 minutes. Stirred reaction at room temperature for 60 minutes then heated it at 90xc2x0 C.-95xc2x0 C. for 6.0 hours. Cooled reaction to room temperature, filtered precipitates, washed cake with toluene (50.0 mL) and concentrated filtrate to provide the title compound as an oil (mass=15.13 g);
1H nmr (CDCl3) xcex4 0.6-0.8 (b, 1H), 1.5-1.6 (m, 1H), 1.63-1.69 (m, 1H), 1.9-2.0 (m, 2H, 2.0-2.1 (m, 2H), 3.05-3.1 (m, 1H), 3.4-3.7 (m, 1H), 7.19-7.35 (aromatic, 5H); 13C (CDCl3) xcex4 23.05, 27.96, 34.98, 51.75, 56.68, 126.86, 128.96, 129.20, 142.00).

Preparation of (+,xe2x88x92) Trans-2-p-tolyl-cyclopentanol.
Scheme IB, step A: The title compound was prepared in a manner analogous to the procedure described in preparation 8, Scheme IB, step A, starting with 10.0 mL of a 1M ethereal solution of p-tolylphenylmagnesium bromide(100.0 mmol). The same workup gave 1.7 g of a crude yellow oil. The intermediate title compound was purified by radial chromatography eluting with 25:75 EtOAc:hexanes to give 1.48 g (84%) as a colorless oil.
1H nmr (CDCl3) xcex4 1.6-1.84 (m, 4H), 2.0-2.2 (m, 2H), 2.30 (s, 3H), 2.78-2.85 (m, 1H), 4.07-4.13 (m, 1H), 7.09-7.17 (aromatic, 4H).
Preparation of (+,xe2x88x92) Cis-2-(2-p-tolyl-cyclopentyl)-isoindole-1,3-dione.
Scheme IB, step B: The title compound was prepared in a manner analogous to the procedure described in preparation 8, Scheme IB, from (+,xe2x88x92) trans-2-p-tolyl-cyclopentanol (1.48 g, 8.4 mmol, prepared above). Following the same workup gave a crude yellow oil which was triturated with ethyl acetate and the triphenylphosphine oxide removed by filtration. The title compound was purified by radial chromatography eluting with ethyl acetate and then again eluting with methylene chloride to give 0.69 g (27%) of the intermediate title compound as an oil which solidified under vacuum.
1H nmr (CDCl3) xcex4 1.6-1.73 (m, 1H), 1.88-2.03 (m, 1H), 2.10 (s, 3H), 2.15-2.22 (m, 2H), 2.4-2.6 (m, 2H), 3.32-3.41 (m, 1H), 4.95-5.01 (m, 1H), 6.82 (d, 2H, J=9 Hz), 7.00 (d, 2H, J=9 Hz), 7.52-7.62 (m, 4H); Analysis calculated for C20H19NO2xc3x970.2 H2O: % C, 77.75; % H, 6.33; % N, 4.53. Found: % C, 77.93; % H, 6.18; % N, 4.57.
Preparation of the Final Title Compound.
Scheme IB, step C: To (+,xe2x88x92) cis-2-(2-p-tolyl-cyclopentyl)-isoindole-1,3-dione (582 mg, 1.91 mmol, prepared above) was added ethanolamine and the solution was heated to 80xc2x0 C. and stirred for 30 minutes. ES-MS indicated the reaction was not complete and the reaction was heated to 90xc2x0 C. for 30 minutes. The reaction was diluted with ethyl ether and washed with dilute sodium hydroxide, brine and the organic layer dried over sodium sulfate. The filtrate was concentrated to provide 313 mg (94%) of the final title compound, (+,xe2x88x92) cis-2-p-tolyl-cyclopentylamine, as a colorless oil.
Mass Spectrum (ES MS): M+1=176.

Scheme IB, Step A: A 500 mL three necked flask equipped with a mechanical stirrer, thermometer, addition funnel under a blanket of nitrogen was charged with 4-bromophenylmagnesium bromide (43.6 g, 167.57 mmol), anhydrous THF (120.0 mL) and catalytic copper iodide (1.59 g, 8.38 mmol) with vigorous stirring at room temperature for 10.0 minutes. To this mixture was then added dropwise a solution of cyclopentene oxide (14.62 mL, 167.57 mmol) dissolved in THF (20.0 mL) over a period of 20.0 minutes. Reaction was quite exothermic, reaching the reflux of THF by the end of addition. The reaction was brought to room temperature and stirred for 120.0 minutes, after which reaction was reversed quenched carefully into a 25% ammonium chloride solution (100.0 mL). Extracted with methylene chloride (150.0 mL), dried with anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to give an oil (19.0 g). Silica gel plug filtration of the oil with 1:1 ethyl acetate and hexane, and subsequent concentration of fractions 2 and 3 afforded the bromophenylcyclopentyl carbinol as a light red oil (mass=13.61 g, 34% wt. Yield;
1H NMR (CDCl3) xcex4 1.60-2.20 (m, 6H), 2.80-2.90 (m, 1H), 4.10-4.20 (m, 1H), 7.10 (d, 2H), 7.40-7.50 (d, 2H); 13C NMR (CDCl3) xcex4 22.38, 32.45, 54.40, 80.98, 121.00, 129.86, 132.25, 143.00.
Scheme IB, step B: A 500 mL three necked flask equipped with a mechanical stirrer, thermometer, addition funnel under a blanket of nitrogen was charged with triphenylphosphine (8.75 g, 32.68 mmol) and THF (200.0 mL). To this solution at 5xc2x0 C. was added dropwise a solution of diisopropylazodicarboxylate (6.43 mL, 32.68 mmol) dissolved in THF (10.0 mL) over a period of 10.0 minutes (reaction exothermed to 35xc2x0 C.). Stirred for 5.0 minutes then added phthalimide (4.80 g, 32.68 mmol) with vigorous stirring (a massive off yellow precipitate formed). To this mixture was then added a solution of bromophenylcyclopentyl carbinol (7.84 g, 32.68 mmol) dissolved in THF (40.0 mL) over a period of 30.0 minutes maintaining temperature at 5xc2x0 C. (precipitate went into solution by the end of addition). Stirred reaction to room temperature overnight, then quenched with water (250.0 mL) and extracted with methylene chloride (250.0 mL). The organic solution was then dried with anhydrous magnesium sulfate, filtered, and concentrated filtrate to an oil. Added ethyl ether(60.0 mL) with stirring, filtered off triphenylphosphine oxide precipitates and concentrated filtrate to an oil. Silica gel plug filtration of the oil with 1:1 ethyl acetate and hexane and subsequent concentration of fractions 2 and 3 afforded the bromophenylcyclopentyl phthalimido as an oil which solidified on equilibrating to room temperature, mass=3.47 g, 29% wt. Yield;
1H NMR (CDCl3) xcex4 1.03-1.77 (m, 1H), 2.00-2.09 (m, 1H), 2.16-2.27 (m, 2H), 2.35-3.32 (m, 2H), 7.00 (d, 2H), 7.2. (d, 2H), 7.57-7.67 (m, 4H); 13C NMR (CDCl3) xcex4 25.17, 28.93, 30.58, 49.59, 54.00, 119.96, 122.78, 129.83, 130.79, 131.23, 133.67, 138.48, 168.43.
Scheme IB, step C: A 250 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer and an addition funnel was charged with bromophenylcyclopentyl phthalimido (3,47 g, 9.32 mmol), toluene (150 mL) and anhydrous hydrazine (5.0 mL) at room temperature. The reaction was stirred for 120 minutes, then heated at 90xc2x0 C.-95xc2x0 C. for 180 minutes (an off yellow precipitate was formed). Concentrated reaction mixture to a constant weight by removing organic solvents. Added fresh toluene (150.0 mL) with stirring, filtered off precipitates, then concentrated filtrate to provide the free base of the title compound as an oil, mass=1.75 g, 75.3% wt. Yield.
1H NMR (CDCl3) xcex4 0.86 (b, 2H), 1.50-1.60 (m, 1H), 1.60-1.79 (m, 1H), 1.80-2.00 (m, 4H), 3.00 (m, 1H), 3.5 (m, 1H), 7.10 (d, 2H), 7.4 (d, 2H); 13C NMR (CDCl3) xcex4 21.3, 28.00, 31.00, 36.20, 120.00, 128.00, 131.00, 132.00, 141.00.
The above free base of the title compound (1.59 g) was dissolved in ethyl acetate (50 mL) and treated with oxalic acid (0.59 g, 1.0 eq). The slurry was stirred for 60 minutes, concentrated to provide an off yellow solid, treated with ethyl acetate (80.0 mL) with stirring, filtered, and the precipitate was dried under house vacuum at 35xc2x0 C. to provide the title compound (1.04 g).
1H NMR (DMSO) xcex4 1.60-1.80 (m, 2H), 1.81-1.99 (m, 2H), 2.10-2.15 (m, 2H), 3.25-3.10 (m, 1H), 3.69-3.75 (m, 1H); 13C NMR (DMSO) xcex4 22.66, 28.29, 31.11, 48.00, 55.74, 121.45, 132.08, 132.54, 138.41, 165.53.

Scheme IB: The title compound was prepared from 4-chlorophenylmagnesium bromide and cyclopentene oxide in a manner analogous to the procedure described in preparation 10.

The title compound was prepared from 3,5-difluorophenylmagnesium bromide and cyclopentene oxide in a manner analogous to the procedure described in preparation 10.

The title compound was prepared from 4-fluorophenylmagnesium bromide and cyclopentene oxide in a manner analogous to the procedure described in preparation 10.

The title compound was prepared from 3-fluorophenylmagnesium bromide and cyclopentene oxide in a manner analogous to the procedure described in preparation 10.

The title compound was prepared from 3,4-difluorophenylmagnesium bromide and cyclopentene oxide in a manner analogous to the procedure described in preparation 10.

4-Carboxyphenylboronic acid (10.0 g, 60.3 mmol) was suspended in 100 mL of toluene and pinnacol added (7.1 g, 60.3 mmol). The reaction was heated to reflux with a Dean-Stark trap attached. The reaction became homogenous upon heating. After 2 h reflux the reaction was allowed to stand overnight and white needles were collected by filtration and rinsed with toluene. The title compound was vacuum dried to 12.2 g (81%).
Mass Spectrum (FD MS): M=248. Analysis calculated for C13H17BO4: % C, 62.94; % H, 6.91; Found: % C, 62.71; % H, 6.91.

The acid from preparation 16 (6.0 g, 24.2 mmol) was suspended in 20 mL of thionyl chloride, 3 drops of DMF added and the reaction heated to reflux under nitrogen. The solid dissolved upon warming. After refluxing 2 h the reaction was concentrated in vacuo and dried to a white solid under vacuum. The acid chloride was dissolved in 30 mL of THF and cooled to 0xc2x0 C. 40% aqueous methylamine (10.4 mL) was added dropwise. After the addition was complete the ice bath was removed and stirring continued for 30 min. The reaction was concentrated in vacuo (3xc3x971:1 EtOAc:toluene) then extracted with ether/water. The organic layer was dried over sodium sulfate, filtered and concentrated to 5.2 g (83%) of the title compound as a white solid.
Mass Spectrum (FD MS): M=261. Analysis calculated for C14H20BNO3: % C, 64.40; % H, 7.72; % N, 5.36. Found: % C, 64.09; % H, 7.70, % N, 5.28.

Scheme IB, step E: Into a 250 mL 3 neck flask fitted with a stirrer and thermometer was placed 5.00 g (24.7 mmol) of DEAD and 3.50 g (28.7 mmol) benzoic acid in THF (50 mL). 5.78 g (24.0 mmol) of the alcohol from preparation 10 and 7.50 g. (28.6 mmol) of triphenylphosphine in THF (50 mL) was added dropwise while stirring at 0xc2x0 C. under a nitrogen atmosphere. After 2 hours at this temperature, TLC showed that the reaction was complete. Solution was let warm to room temperature and then concentrated under reduced vacuum to yield 9.14 g of an oil. This material was purified via silica gel chromatography employing the Water""s prep. 2000 and eluting with an isocratic solvent of hexane/methylene chloride 1:1 to yield 3.74 g (45%) of title compound as a slowly crystallizing oil. Ion spray M.S. 344 (M*xe2x88x921): Calculated for: C18H17O2Br Theory: C 62.62, H 4.96 Found: C 62.40, H 4.90.

Scheme IB, step F: To the compound prepared in preparation 18, 3.70 g (10.7 mmol) was added 5% NaOH/MeOH (75 mL, excess) in a 250 mL single-neck flask and stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure to yield a semi-solid. This material was taken into ether and washed once with water, dried over potassium carbonate, and concentrated under reduced vacuum to yield 3.01 g of an oil. This material was purified via silica gel chromatography employing the Water""s prep. 2000 and eluting with an isocratic solvent of hexane/methylene chloride 1:1 to yield 2.31 g (90%) of a clear oil. NMR was consistent with the proposed structure. Ion spray M.S. 241 (M*): Calculated for: C11H13OBr. Theory: C 54.79, H 5.43 Found: C 54.91, H 5.12.

Scheme IB, step G: Into a 500 mL 3N flask fitted with a stirrer and thermometer, 8.49 g (42.0 mmol) of DEAD in THF (25 mL) was added dropwise to 10.37 g (42.0 mmol) of triphenylphosphine in THF (175 mL) while stirring at 0xc2x0 C. under a nitrogen atmosphere. A white precipitate formed. At this same temperature, 6.18 g (42.0 mmol) of phthalimide in THF (25 mL) was added dropwise followed by 10.15 g (42.0 mmol) of the compound prepared in preparation 19 in THF (25 mL) added dropwise at 0xc2x0 C. The reaction was then stirred at this temperature for 4 hours and then allowed to warm to room temperature. The mixture was poured into water and the desired material was extracted with ethyl acetate. The organic layer was washed once with water, dried over potassium carbonate, and concentrated under reduced vacuum to yield 27.31 g of a semi-solid. This material was extracted with 3-500 mL portions of hexane and filtered. The filtrate was concentrated under reduced vacuum to yield 14.71 g of a yellow solid. This material was purified via silica gel chromatography employing the Water""s prep. 2000 and eluting with an isocratic solvent of hexane/ethyl acetate 9:1 to yield 5.20 g (34%) of a white solid. Ion spray M.S. 372.1 (M*+2):
Calculated for: C19H16NO2Br; Theory: C 61.61, H 4.36, N 3.78; Found: C 61.41, H 4.24, N 3.81.

Scheme IB, step H: Into a 250 mL 3N flask fitted with a stirrer, thermometer, and condenser was placed 5.10 g (14 mmol) of (+,xe2x88x92) trans 2-[2-(4-bromo-phenyl)-cyclopentyl]-isoindole-1,3-dione in toluene (60 mL), prepared in preparation 20. To this mixture was added dropwise 4.50 g (140 mmol) of hydrazine in toluene (2 mL) while stirring at room temperature under a nitrogen atmosphere. The reaction was then heated at 95xc2x0 C. for 6 hours. The reaction was cooled to room temperature and stirred overnight. In the morning, the precipitate that had formed was filtered and the filtrate was dried over potassium carbonate and then concentrated under reduced vacuum to yield 3.41 g of an oil. This material was purified via silica gel chromatography employing the Water""s prep. 2000 and eluting with an isocratic solvent of methylene chloride/methanol 9:1 to yield (+,xe2x88x92) trans 2-(4-bromo-phenyl)-cyclopentylamine (3.30 g, 98%) as a light oil. Ion spray M.S. 239.1 (M*xe2x88x921):
Calculated for: C11H14NBr; Theory: C 55.01, H 5.87, N 5.83; Found: C 53.18, H 5.50, N 5.39.

4-Aminobenzoic acid (5.0 g, 36.46 mmol) in 500 mL 3-neck round bottomed flask, fitted with a condenser, thermometer, addition funnel, stir bar, and nitrogen atmosphere, was dissolved in ethanol (100 mL). Next ethanol/HCl saturate (from bubbling concentrated HCl through ethanol) was added dropwise, by addition funnel. Then stirred at reflux for 1 h, cooled to room temperature, and stirred an additional 104 hours. Reaction mixture was then concentrated under reduced vacuum, and dissolved in ethyl acetate, and washed with water (2xc3x9750 mL), dried (K2CO3), filtered and concentrated under reduced vacuum, yielding 3.56 g of an off-white solid. This material was purified by silica gel chromatography, using a Waters HPLC Prep 2000, over one Prep-Pak, in a 1:1 hexanes:ethyl acetate solvent system, yielding the title compound as 2.35 g (39%) as a white solid.
Electrospray-MS 166.0 (M*+1).

3-Aminobenzoic acid (5.0 g, 36.46 mmol) in 500 mL 3-neck round bottomed flask, fitted with a condenser, thermometer, addition funnel, stir bar, and nitrogen atmosphere, was dissolved in ethanol (100 mL). Next ethanol/HCl saturate (from bubbling concentrated HCl through ethanol) was added dropwise, by addition funnel. Then stirred at reflux for 1 h, cooled to room temperature, and stirred an additional 84 hours. Reaction mixture was then concentrated under reduced vacuum, and dissolved in ethyl acetate, and washed with water (2xc3x9750 mL), dried (K2CO3), filtered and concentrated under reduced vacuum, yielding 1.14 g of a brown oil. This material was purified by silica gel chromatography, using a Chromatotron(copyright) with a 6000 uM rotor, in a 1:1 hexanes:ethyl acetate solvent system, yielding the title compound as 1.24 g (21%) brown oil.
Electrospray-MS 166.0 (M*+1).

The amine prepared in preparation 22 (2.35 g, 14.23 mmol), di-tert-butyl dicarbonate (3.42 g, 15.65 mmol), and methylene chloride (100 mL) were combined into a 250 mL round bottomed flask, fitted with a stirbar, and under a nitrogen atmosphere, and stirred at room temperature for 15 minutes. Then added dimethylaminopyridine (610 mg, 0.35 mmol), and stirred for an additional hour. The reaction mixture was then quenched with water (100 mL), separated by separatory funnel, dried the organic layer (MgSO4), filtered, and concentrated under reduced vacuum, yielding 3.66 g of a slow crystallizing yellow oil. This material was purified by silica gel chromatography, using a Waters HPLC Prep 2000 with one Prep-Pak, in a 1:1 hexanes:ethyl acetate solvent system, yielding the title compound as 1.3 g (34%) white crystals.
Electrospray-MS 266.0 (M*+1).

The amine prepared in preparation 23 (1.24 g, 7.51 mmol), di-tert-butyl dicarbonate (1.80 g, 8.26 mmol), and methylene chloride (50 mL) were combined into a 250 mL round bottomed flask, fitted with a stirbar, and under a nitrogen atmosphere, and stirred at room temperature for 15 minutes. Then added dimethylaminopyridine (610 mg, 0.35 mmol), and stirred for an additional hour. The reaction mixture was then quenched with water (100 mL), separated by separatory funnel, drying the organic layer (MgSO4), filtered, and concentrated under reduced vacuum, yielding 2.06 g brown oil. This material was purified by silica gel chromatography, using a Waters HPLC Prep 2000 with one Prep-Pak, in a 1:1 hexanes:ethyl acetate solvent system, yielding the title compound as 750 mg (38%) brown oil.
Electrospray-MS 266.0 (M*+1).

The ester prepared in preparation 24 (1.3 g, 4.90 mmol), lithium hydroxide (720 mg, 17.15 mmol), methanol (24.5 mL), water (24.5 mL), and tetrahydrofuran (73.5 mL), were combined in a 250 mL round bottomed flask, fitted with a stirbar, and under a nitrogen atmosphere. The mixture was stirred vigorously at room temperature for 16 hours, then concentrated under vacuum, dissolved in 1N HCl, and extracted with methylene chloride (100 mLxc3x973). Organic layer was next dried (MgSO4), filtered, and concentrated under vacuum, yielding 1.07 g of white solid. This material was purified by silica gel chromatography, using a Chromatotron(copyright) with a 6000 uM rotor, in a 1:1 hexanes:ethyl acetate solvent system, yielding the title compound as 440 mg (38%) white solid.
Electrospray-MS 238.0 (M*+1).

The ester prepared in preparation 25 (750 mg, 2.83 mmol), lithium hydroxide (415 mg, 9.89 mmol), methanol (15 mL), water (15 mL), and tetrahydrofuran (45 mL), were combined in a 250 mL round bottomed flask, fitted with a stirbar, and under a nitrogen atmosphere. The mixture was stirred vigorously at room temperature for 16 hours, then was concentrated under vacuum, dissolved in 1N HCl, and extracted with methylene chloride (100 mLxc3x973). Organic layer was dried (MgSO4), filtered, and concentrated under vacuum, yielding 600 mg of white solid. This material was purified by recrystallization in hexanes:ethyl acetate, yielding the title compound as 580 mg (86%) white solid.
Electrospray-MS 238.0 (M*+1).

Scheme IC: A solution of (+,xe2x88x92)-2-(4-bromophenyl)cyclopentanol (250.5 g, 1.04 moles) in 250 ml MTBE is added to 16 grams immobilized Candida antarctica B lipase (Roche Molecular Biochemicals CHIRAZYME(copyright) L-2, c.-f. C2, lyo,  greater than 3200 units). With stirring, vinyl acetate (51.7 g, 0.60 mole) is added. This mixture is stirred under nitrogen at ambient temperature with periodic HPLC analysis (Zorbax SB-Phenyl, 250xc3x9746 mm, 35% 0.1% H3PO4:65% acetonitrile, 1.0 ml/min, xcex=220 nm). Acylation is complete in 180 minutes. Immobilized enzyme is removed by gravity filtration, and the filtrate is evaporated in vacuo to provide 247.6 g (90.9%) of a 1:1 mixture of (1S,2R)-2-(4-bromophenyl)cyclopentanol (compound A) and (1R,2S)-1-acetoxy-2-(4-bromophenyl)cyclopentane (compound B).
Compound A; 1H NMR (CDCl3) xcex4 1.19-1.25 (m, 2H), 1.68-1.71 (m, 1H), 1.72-1.80 (m, 1H), 1.98-2.06 (m, 3H), 2.95-2.99 (m, 1H), 4.24-4.26 (m, 1H), 7.16-7.18 (d, 2H, J=8.54 Hz), 7.44-7.46 (d, 2H, J=8.30 Hz); 13C NMR (CDCl3) xcex4 22.56, 27.84, 34.25, 51.62, 75.81, 120.65, 128.70, 128.76, 128.95, 130.62, 131.72, 133.89, 134.05, 139.33.
Compound B; 1H NMR (CDCl3) xcex4 1.61-1.70 (m, 2H), 1.71-1.81 (m, 2H), 1.82-1.84 (m, 2H), 2.03 (s, 3H), 2.11-2.21 (m, 2H), 3.08-3.11 (m, 1H), 5.05-5.08 (m, 1H), 7.08-7.12 (d, 2H, J=8.24 Hz), 7.39-7.42 (d, 2H, J=8.54 Hz); 13C NMR (CDCl3) xcex4 21.35, 22.78, 31.95, 32.05, 50.59, 81.67, 120.07, 128.42, 128.93, 131.40, 131.92, 141.62, 170.65.